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Kalbitor(ecallan-tide)-首个获得FDA批准用于治疗遗传性血管性水肿(HAE)的皮下制剂
Immunogenicity In the Kalbitor HAE program, patients developed antibodies to Kalbitor. Rates of seroconversion increased with exposure to Kalbitor over time. Overall, 20.2% of patients seroconverted to anti-ecallantide antibodies. Neutralizing antibodies to ecallantide were determined in vitro to be present in 8.8% of patients and were not associated with loss of efficacy. Anti-ecallantide IgE antibodies were detected at a rate of 4.7% for tested patients, and anti- P. pastoris IgE antibodies were also detected at a rate of 20.2%. Patients who seroconvert may be at a higher risk of a hypersensitivity reaction. The long-term effects of antibodies to Kalbitor are not known. The test results for the ecallantide program were determined using one of two assay formats: ELISA and bridging electrochemiluminescence (ECL). As with all therapeutic proteins, there is a potential for immunogenicity with the use of Kalbitor. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Kalbitor with the incidence of antibodies to other products may be misleading. Postmarketing Experience Similar adverse reactions have been observed postmarketing as described for clinical trial experience. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or to establish a causal relationship with drug exposure. 7 DRUG INTERACTIONS No formal drug interactions studies were performed. No in vitro metabolism studies were performed. 8 USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled trials of Kalbitor in pregnant women. Kalbitor has been shown to cause developmental toxicity in rats, but not rabbits. Because animal reproductive studies are not always predictive of human response, Kalbitor should be used during pregnancy only if clearly needed. In rats, intravenous Kalbitor at an intravenous dose approximately 13 times the maximum recommended human dose (MRHD) (on a mg/kg basis at a maternal dose of 15 mg/kg/day in rats) caused increased numbers of early resorptions and percentages of resorbed conceptuses per litter in the presence of mild maternal toxicity. No development toxicity was observed in rats that received an intravenous dose approximately 8 times the MRHD (on a mg/kg basis at a maternal dose of 10 mg/kg/day in rats). There were no adverse effects of Kalbitor on embryofetal development in rats that received subcutaneous doses up to approximately 2.4 times the MRHD (on an AUC basis at a maternal dose of 20 mg/kg/day in rats), and in rabbits that received intravenous doses up to approximately 6 times the MRHD (on an AUC basis at a maternal dose of 5 mg/kg/day in rabbits). Labor and Delivery No information is available on the effects of Kalbitor during labor and delivery. Nursing Mothers It is not known whether ecallantide is excreted in human milk. Caution should be exercised when ecallantide is administered to a nursing woman. Pediatric Use The safety and effectiveness of Kalbitor have been established in patients 12 to 17 years of age. The efficacy of Kalbitor in the 12-15 year age group is extrapolated from efficacy in patients 16 years of age and older with support from population pharmacokinetic analyses showing similar drug exposure levels in adults and adolescents [ see Clinical Pharmacology (12.3) and Clinical Studies (14)]. The safety profile observed in pediatric patients 12-17 years of age was similar to the adverse reactions observed in the overall clinical trial population [ see Adverse Reactions (6.1)]. Safety and effectiveness of Kalbitor in patients less than 12 years of age have not been established. Geriatric Use Clinical trials of Kalbitor did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 10 OVERDOSAGE There have been no reports of overdose with Kalbitor. HAE patients have received single doses up to 90 mg intravenously without evidence of dose-related toxicity. 11 DESCRIPTION Kalbitor (ecallantide) is a human plasma kallikrein inhibitor for injection for subcutaneous use. Ecallantide is a 60-amino-acid protein produced in Pichia pastoris yeast cells by recombinant DNA technology. Kalbitor is a clear and colorless, sterile, and nonpyrogenic solution. Each vial contains 10 mg ecallantide as the active ingredient, and the following inactive ingredients: 0.76 mg disodium hydrogen orthophosphate (dihydrate), 0.2 mg monopotassium phosphate, 0.2 mg potassium chloride, and 8 mg sodium chloride in water for injection, USP. Kalbitor is preservative free, with a pH of approximately 7.0. A 30 mg dose is supplied as 3 vials each containing 1 mL of 10 mg/mL Kalbitor. Vials are intended for single use. 12 CLINICAL PHARMACOLOGY Mechanism of Action Hereditary angioedema (HAE) is a rare genetic disorder caused by mutations to C1-esterase-inhibitor (C1-INH) located on Chromosome 11q and inherited as an autosomal dominant trait. HAE is characterized by low levels of C1-INH activity and low levels of C4. C1-INH functions to regulate the activation of the complement and intrinsic coagulation (contact system pathway) and is a major endogenous inhibitor of plasma kallikrein. The kallikrein-kinin system is a complex proteolytic cascade involved in the initiation of both inflammatory and coagulation pathways. One critical aspect of this pathway is the conversion of High Molecular Weight (HMW) kininogen to bradykinin by the protease plasma kallikrein. In HAE, normal regulation of plasma kallikrein activity and the classical complement cascade is therefore not present. During attacks, unregulated activity of plasma kallikrein results in excessive bradykinin generation. Bradykinin is a vasodilator which is thought by some to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain. Kalbitor is a potent (Ki = 25 pM), selective, reversible inhibitor of plasma kallikrein. Kalbitor binds to plasma kallikrein and blocks its binding site, inhibiting the conversion of HMW kininogen to bradykinin. By directly inhibiting plasma kallikrein, Kalbitor reduces the conversion of HMW kininogen to bradykinin and thereby treats symptoms of the disease during acute episodic attacks of HAE. Pharmacodynamics No exposure-response relationships for Kalbitor to components of the complement or kallikrein-kinin pathways have been established. The effect of Kalbitor on activated partial thromboplastin time (aPTT) was measured because of potential effect on the intrinsic coagulation pathway. Prolongation of aPTT has been observed following intravenous dosing of Kalbitor at doses ≥20 mg/m 2. At 80 mg administered intravenously in healthy subjects, aPTT values were prolonged approximately two-fold over baseline values and returned to normal by 4 hours post-dose. For patients taking Kalbitor, no significant QT prolongation has been seen. In a randomized, placebo-controlled trial (EDEMA4) studying the 30 mg subcutaneous dose versus placebo, 12-lead ECGs were obtained at baseline, 2 hours and 4 hours post-dose (covering the time of expected C max), and at follow-up (day 7). ECGs were evaluated for PR interval, QRS complex, and QTc interval. Kalbitor had no significant effect on the QTc interval, heart rate, or any other components of the ECG. Pharmacokinetics Following the administration of a single 30 mg subcutaneous dose of Kalbitor to healthy subjects, a mean (± standard deviation) maximum plasma concentration of 586 ± 106 ng/mL was observed approximately 2 to 3 hours post-dose. The mean area under the concentration-time curve was 3017 ± 402 ng*hr/mL. Following administration, plasma concentration declined with a mean elimination half-life of 2.0 ± 0.5 hours. Plasma clearance was 153 ± 20 mL/min and the volume of distribution was 26.4 ± 7.8 L. Based on a population pharmacokinetic analysis, body weight, age, and gender were not found to affect Kalbitor exposure significantly. Ecallantide is a small protein (7054 Da) and renal elimination in the urine of treated subjects has been demonstrated. No pharmacokinetic data are available in patients or subjects with hepatic or renal impairment. 13 NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year study was conducted in rats to assess the carcinogenic potential of Kalbitor. No evidence of tumorigenicity was observed in rats at ecallantide doses up to 10 mg/kg administered subcutaneously every three days (approximately 2-fold greater than the MRHD on an AUC basis). Kalbitor had no effects on fertility and reproductive performance in rats at subcutaneous doses up to 25 mg/kg/day (approximately 21 times the MRHD on a mg/kg basis). 14 CLINICAL STUDIES The safety and efficacy of Kalbitor to treat acute attacks of hereditary angioedema in adolescents and adults were evaluated in 2 randomized, double-blind, placebo-controlled trials (EDEMA4 and EDEMA3) in 168 patients with HAE. Patients having an attack of hereditary angioedema, at any anatomic location, with at least 1 moderate or severe symptom, were treated with 30 mg subcutaneous Kalbitor or placebo. Because patients could participate in both trials, a total of 143 unique patients participated. Of the 143 patients, 94 were female, 123 were Caucasian, and the mean age was 36 years (range 11-77). There were 64 patients with abdominal attacks, 55 with peripheral attacks, and 24 with laryngeal attacks. In both trials, the effects of Kalbitor were evaluated using the Mean Symptom Complex Severity (MSCS) score and the Treatment Outcome Score (TOS). These endpoints evaluated attack severity (MSCS) and patient response to treatment (TOS) for an acute HAE attack. MSCS score is a point-in-time measure of symptom severity. At baseline, and post-dosing at 4 hours and 24 hours, patients rated the severity of each affected symptom on a categorical scale (0 = normal, 1 = mild, 2 = moderate, 3 = severe). Patient-reported severity was based on each patient’s assessment of symptom impact on their ability to perform routine activities. Ratings were averaged to obtain the MSCS score. The endpoint was reported as the change in MSCS score from baseline. A decrease in MSCS score reflected an improvement in symptom severity; the maximum possible change toward improvement was -3. TOS is a measure of symptom response to treatment. At 4 hours and 24 hours post-dosing, patient assessment of response for each anatomic site of attack involvement was recorded on a categorical scale (significant improvement [100], improvement [50], same [0], worsening [-50], significant worsening [-100]). The response at each anatomic site was weighted by baseline severity and then the weighted scores across all involved sites were averaged to calculate the TOS. A TOS value >0 reflected an improvement in symptoms from baseline. The maximum possible score was +100. EDEMA4 EDEMA4 was a randomized, double-blind, placebo-controlled trial in which 96 patients were randomized 1:1 to receive Kalbitor 30 mg subcutaneous or placebo for acute attacks of HAE. The primary endpoint was the change from baseline in MSCS score at 4 hours, and the TOS at 4 hours was a key secondary endpoint. Patients treated with Kalbitor demonstrated a greater decrease from baseline in the MSCS than placebo and a greater TOS than patients with placebo and the results were statistically significant (Table 2). At 24 hours, patients treated with Kalbitor also demonstrated a greater decrease from baseline in the MSCS than placebo (-1.5 vs. -1.1; p = 0.04) and a greater TOS (89 vs. 55, p = 0.03). Table 2: Change in MSCS Score and TOS at 4 Hours
Some patients reported improvement following a second 30 mg subcutaneous dose of Kalbitor, administered within 24 hours following the initial dose for symptom persistence or relapse, but efficacy was not systematically assessed for the second dose. EDEMA3 EDEMA3 was a randomized, double-blind, placebo-controlled trial in which 72 patients were randomized 1:1 to receive Kalbitor or placebo for acute attacks of HAE. EDEMA3 was similar in design to EDEMA4 with the exception of the order of the prespecified efficacy endpoints. In EDEMA3, the primary endpoint was the TOS at 4 hours, and the key secondary efficacy endpoint was the change from baseline in MSCS at 4 hours. As in EDEMA4, patients treated with Kalbitor demonstrated a greater decrease from baseline in the MSCS than placebo and a greater TOS than patients treated with placebo and the results were statistically significant (Table 2). In addition, more patients in the placebo group (13/36, 36%) required medical intervention to treat unresolved symptoms within 24 hours compared to the Kalbitor-treated group (5/36, 14%). 16 HOW SUPPLIED/STORAGE AND HANDLING Kalbitor (ecallantide) is supplied as three 10 mg/mL single-use vials packaged in a carton. Each vial contains 10 mg of ecallantide. Each vial contains a slight overfill. •NDC (47783-101-01): 3 single-use vials in 1 carton Kalbitor should be kept refrigerated (2ºC to 8ºC/36ºF to 46ºF). Vials removed from refrigeration should be stored below 86ºF/30ºC and used within 14 days or returned to refrigeration until use. Protect vials from light until use. Do not use beyond the expiration date. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guid •Advise patients that Kalbitor may cause anaphylaxis and other hypersensitivity reactions. Advise patients that Kalbitor should be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and hereditary angioedema. Instruct patients who have known clinical hypersensitivity to Kalbitor not to receive additional doses of Kalbitor. [ see Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)] •Advise patients to consult the Medication Guide for additional information regarding the risk of anaphylaxis and other hypersensitivity reactions. Dyax公司遗传性血管水肿新药DX-2930获FDA突破性药物 生物制药公司Dyax研发的一款治疗遗传性血管水肿（HAE）的药物DX-2930近日收获FDA的突破性疗法认定（BTD）。DX-2930是一种全人源化单克隆抗体，靶向抑制血浆激肽释放酶（pKal），目前正开发作为一种皮下注射药物，用于预防HAE的发作。 突破性疗法认定（BTD）旨在加速开发及审查针对严重或危及生命的疾病具有治疗潜力的新药。获得BTD的药物，在研发时能得到包括FDA高层官员在内的更加密切的指导，保障在最短时间内为患者提供新的治疗选择。 FDA授予DX-2930突破性疗法认定，是基于在遗传性血管水肿（HAE）患者中开展的一项Ib期临床试验的积极数据。数据显示，与安慰剂相比，DX-2930显著降低了患者每周HAE发作的平均次数。此外，该研究也达到了安全性、耐受性、多次皮下注射DX-2930的药代动力学等所有目标。Dyax已计划在今年晚些时候启动一项II期临床研究。 事实上，Dyax公司早在2009年就推出了一款皮下注射药物Kalbitor，该药是继Berinert（一种来源于血浆的C1酯酶抑制剂）之后FDA批准的第2种HAE治疗药物，也是首个治疗急性HAE发作的皮下注射药物。去年4月，FDA进一步批准扩大Kalbitor的适用人群，用于12岁及以上HAE患者。Kalbitor上市之后，竞争对手Shire和Salix也推出了各自的HAE治疗产品。据Dyax公布的数据，Kalbitor在去年的销售额为6500万美元。 除了HAE，Dyax目前也正在调查血浆激肽释放酶（pKal）相关的疾病，将其专有的技术用于糖尿病性黄斑水肿、炎症性肠病、类风湿性关节炎及其他疾病的潜在治疗。DX-2930是一种新型的全人源化单克隆抗体，靶向抑制pKal。不受控的pKal活动可导致缓激肽（bradykinin）的过度生成，这是一种血管扩张剂，可引发HAE相关的局部肿胀、炎症及疼痛。 遗传性血管水肿（HAE）是一种罕见的、遗传性、急性炎症性疾病，致病基因为C1酯酶抑制剂（C1-INH）基因，该基因突变导致患者血清中C1酯酶抑制因子减少或功能缺陷，不足以抑制缓激肽生成级联反应，而使体内大量缓激肽生成引发血管通透性增高、血浆外渗，进而引起局部组织水肿。该病临床表现为反复发作的皮肤和黏膜下水肿，可累及四肢、颜面、外生殖器、呼吸道或消化道黏膜。患者常因肠道水肿引发腹部剧烈疼痛及其他消化道症状。而呼吸道黏膜水肿可导致憋气、呼吸困难，严重者可出现窒息甚至死亡。 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
